In the last 4 years, three "new" influenza strains have appeared in animal populations that have caused severe disease and significant mortality. The probability of this occurring in humans remains real. Chemotherapeutic agents such as amantadine and rimantadine have been shown to provide protection against influenza infection. Potentially, these drugs could be very useful in the control of a severe epidemic. The most effective use of these chemotherapeutic agents depends on an understanding of their mechanism of action and an understanding of the genetic changes that allow the development of drug resistance by the virus. The goal of the proposed research is to provide this understanding. This work will use a highly virulent influenza virus from chickens (Chick/Penn/83) as a model system. This virus system is of interest in its own right and well-suited for this study, because it is a natural system that has been shown to be sensitive to amantadine and to generate amantadine resistant mutants. Specific questions to be asked include: (1) what is the genetic change that occurs when amantadine resistant mutants are generated, and are these drug resistant mutants biologically competent enough to compete with the wild-type virus for susceptible hosts and to cause severe disease; (2) what is the mechanism by which amantadine inhibits influenza virus; (3) does the amantadine related drug, ICI 130,685 have a different specificity than amantadine and rimantadine and are amantadin-resistant mutants sensitive to ICI 130,685.